Lipid membranes trigger misfolding and self-assembly of amyloid β 42 protein into aggregates

Abstract

The assembly of polypeptides and proteins into nanoscale aggregates is a phenomenon observed in a vast majority of proteins. Importantly, aggregation of amyloid {beta} (A{beta}) proteins is considered as a major cause for the development of Alzheimers disease. The process depends on various conditions and typical test-tube experiments require high protein concentration that complicates the translation of results obtained in vitro to understanding the aggregation process in vivo. Here we demonstrate that A{beta}42 monomers at the membrane bilayer are capable of self-assembling into aggregates at physiologically low concentrations, and the membrane in this aggregation process plays a role of a catalyst. We applied all-atom molecular dynamics to demonstrate that the interaction with the membrane surface dramatically changes the conformation of A{beta}42 protein. As a result, the misfolded A{beta}42 rapidly assembles into dimers, trimers and tetramers, so the on-surface aggregation is the mechanism by which amyloid oligomers are produced and spread.